The invention relates to methods and compositions for treating Generalized Anxiety Disorder (GAD) and associated symptoms comprising administering a very low dose of cyclobenzaprine or a metabolite thereof. The invention also relates to compositions comprising a very low dose of cyclobenzaprine or a metabolite thereof.
Cyclobenzaprine
Cyclobenzaprine or 3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, is represented by the chemical formula: 
Cyclobenzaprine was first synthesized in 1961. [Villani, F. J., et al., xe2x80x9cDialkylaminoalkyl derivatives of 10,11-dihydro-511-dibenzo a,d cycloheptene and related compounds,xe2x80x9d J. Med. Pharm. Chem. 5:373-383 (1962)]. Cyclobenzaprine was approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local origin. [Katz, W., et al., xe2x80x9cCyclobenzaprine in the Treatment of Acute Muscle Spasm: Review of a Decade of Clinical Experience,xe2x80x9d Clinical Therapeutics 10:216-228 (1988)]. Cyclobenzaprine is sold as a hydrochloride salt in a 10 mg non-scored tablet under the tradename Flexeril(copyright) (Merck and Co.) or as a generic for use as a skeletal muscle relaxant. The pharmacokinetics of cyclobenzaprine metabolism have been well studied (e.g., Katz, et al., page 219, supra).
No indications of organ toxicity were found in cyclobenzaprine-treated patients at recommended doses. Toxic effects were reported, however, for three individuals who ingested between 260 to 900 mg of cyclobenzaprine. [Katz, et al., xe2x80x9cCyclobenzaprine in the Treatment of Acute Muscle Spasm: Review of a Decade of Clinical Experience,xe2x80x9d Clinical Therapeutics 10:216-228 (1988)]
The principal side effects of cyclobenzaprine treatment are drowsiness, dry mouth or tongue, dizziness and bad taste. [Katz, W. A., et al., supra.] Other less common side effects include nausea, tiredness, constipation, blurred vision, nervousness, confusion, abdominal pain and discomfort.
Generalized Anxiety Disorder
Anxiety disorders are part of a heterogeneous group of psychiatric disorders that are characterized by their predominant symptom being that of anxiety. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (hereinafter, xe2x80x9cDSM-IV(trademark)xe2x80x9d) lists twelve different types of Anxiety Disorders. [American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washingon, D.C., American Psychiatric Association, 1994] These are as follows: Panic Disorder without Agoraphobia; Panic Disorder with Agoraphobia; Agoraphobia without a history of Panic Disorder; Specific Phobia; Social Phobia; Obsessive Compulsive Disorder; Post-traumatic Stress Disorder; Acute Stress Disorder; Generalized Anxiety Disorder; Anxiety Disorder Due to a General Medical Condition; Substance Induced Anxiety Disorder; and Anxiety Disorder not Otherwise Specified.
Generalized Anxiety Disorder (GAD) is the most common anxiety disorder among Americans, though exact incidence and prevalence rates are unknown. People with GAD feel anxious and tense all day long, and their fear is not limited to specific situations. The intensity, duration or frequency of the anxiety and worry is far out of proportion to the actual likelihood or impact of the feared event. The person finds it difficult to keep worrisome thoughts from interfering with attention to tasks at hand and has diffulculty stopping the worry. Adults with GAD often worry about everyday, routine life circumstances (e.g., possible job responsibilities, finances the health of family members, misfortune to their children, or minor matters (such as household chores, car repairs, or being late for appointments).
GAD occurs in both children and adults and was formerly called Overanxious Disorders of Childhood. Children with this disorder tend to worry excessively about their competence or the quality of their work and they may become overly conforming, perfectionist and unsure of themselves. Labellarte, M J, et al, xe2x80x9cThe Treatment of Anxiety Disorders in Children and Adolescents,xe2x80x9d Biol. Psychiatry, 46(11):1567-78 (1999).
Ordinary practitioners in the art (e.g., clinicians and physicians) will often make diagnoses which refer to the GAD as either primary or secondary. These classifications merely indicate whether the most prominent symptoms the patient is experiencing stem from GAD, as is true with a diagnosis of primary GAD, or from another illness or disorder with concomitant symptoms of GAD also emerging, as is the case with secondary GAD. Rogers, M P et al. xe2x80x9cComparing Primary and Secondary Generalized Anxiety Disorder in a long-term Naturalistic Study of Anxiety Disorders,xe2x80x9d Depress Anxiety, 10(1):1-7, (1999).
A diagnosis of GAD is distinguishable from a diagnosis of non-pathological anxiety, other Anxiety disorders (e.g., Anxiety Disorder due to a General Medical Condition, Substance-Induced Anxiety Disorder) and Axis I disorders based on patient history, laboratory findings and/or physical examination. Patients suffering from GAD meet the criteria set forth in DSM-IV(trademark). Thus, patients suffering from GAD, as opposed to non-pathological anxiety, have worries that are more difficult to control, pervasive, pronounced, distressing, longer in duration and typically interfere significantly with functioning. The worries frequently occur without precipitants and are much less likely to be accompanied by physical symptoms in adults. Generally, if the anxiety or worry solely arises etiologically from a general medical condition (e.g., pheochomocytoma, hyperthyroidism) or taking drugs or if the anxiety is confined to a feature of an Axis I disorder, then GAD is not diagnosed. For example, with regard to Axis I Disorders, patients suffering from excessive worry that is confined to having a Panic Attack (Panic Disorder), being embarrassed in public (Social Phobia), being contaminated (Obsessive-Compulsive Disorder), gaining weight (Anorexia Nervosa), having a serious illness (Hypochondriasis), being away from home or from close relations (Separation Anxiety Disorder) would be diagnosed with the appropriate Axis I disorder.
Various drugs including barbiturates and benzodiapines are often prescribed as primary anxiolytics, while antihistamines, tricyclic antidepressants, antipsychotics and beta-blockers have been prescribed for their secondary anxiolyticiolitic properties. These treatments for Generalized Anxiety Disorder have not proved to be satisfactory due to less than sufficient efficacy, distressing side effects, or addictive qualities.
The present invention provides methods for treating a human suffering from GAD using a very low dose of cyclobenzaprine, a metabolite thereof, or a pharmaceutically acceptable salt of cyclobenzaprine or metabolite thereof.
The present invention also provides a composition comprising a very low dose of cyclobenzaprine or a metabolite thereof, prepared as a single unit or pre-prepared as a unit separable into portions, each portion of which comprises a very low dose of cyclobenzaprine or metabolite thereof.
The composition is a dosage form of cyclobenzaprine that is useful for treating GAD and is better and effective for treating patients needing treatment with cyclobenzaprine than previous dosage forms of cyclobenzaprine. The composition also allows practitioners to determine and prescribe the appropriate dosage regimen of cyclobenzaprine with a precision and accuracy previously not possible. A composition according to this invention may additionally comprise one or more therapeutic agents such as barbiturates, benzodiazepines, antihistamines, TCAs, SSRIs, atypical antidepressants, antipsychotics and/or beta-blockers.